No evidence for cumulative effects in a Dnmt3b hypomorph across multiple generations
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Observations of inherited phenotypes that cannot be explained solely through genetic inheritance are increasing. Evidence points to transmission of non-DNA molecules in the gamete as mediators of the phenotypes. However, in most cases it is unclear what the molecules are, with DNA methylation, chromatin proteins, and small RNAs being the most prominent candidates. From a screen to generate novel mouse mutants of genes involved in epigenetic reprogramming, we produced a DNA methyltransferase 3b allele that is missing exon 13. Mice that are homozygous for the mutant allele have smaller stature and reduced viability, with particularly high levels of female post-natal death. Reduced DNA methylation was also detected at telocentric repeats and the X-linked Hprt gene. However, none of the abnormal phenotypes or DNA methylation changes worsened with multiple generations of homozygous mutant inbreeding. This suggests that in our model the abnormalities are reset each generation and the processes of transgenerational epigenetic reprogramming are effective in preventing their inheritance.
KeywordsGreen Fluorescent Protein Expression Bisulphite Sequencing Transgenerational Epigenetic Inheritance Genomic Imprint Litter Size Reduction
The authors thank En Li (China Novartis Institutes for BioMedical Research) for the Dnmt3b knockout mice. This study was supported by Australian NHMRC project grants to EW. ARR and KLL were supported by Australian Postgraduate awards. JMM is supported by an NHMRC Senior Research Fellowship. EW is supported by an NHMRC Australia Fellowship.
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